Abstract

Thyroid hormone plays important roles in eukaryotic cell development,differentiation and metabolism. Among them, the balance between proliferation and differentiation is crucial in TH action in normal and pathological conditions, including cancer. These activities are mediated by nuclear thyroid hormone receptors (TRs). T3 and its receptor in concert with other transcription factors stimulate or repress the expression of target genes, some of which are involved inthe control of cellular proliferation. The modern paradigm of thyroid hormone action also recognizes that thyroid hormone signaling in individual tissues can change also when serum hormone concentrations remain normal, due to local activation or inactivation of thyroid hormone. The underlying mechanism of these phenomena is deiodination. These enzymes can, within the single cell, enhance (D1 and D2) or reduce (D3) T3 concentrations, thereby constituting a potent mechanism of pre-receptorial control of thyroid hormone action . Type 3 deiodinase, the major physiological inactivator of TH, is highly expressed in developing tissues and in some tumoral tissues, with a mostly unknown function. We recently observed that in human and mouse Basal Cell Carcinoma (BCC), a skin tumor caused by the constitutive activation of Shh signaling, a constitutive overexpression of D3. This overexpression is determined by a transcriptional induction of D3 mRNA by Shh/Gli pathway (Fig. 3). Shh- mediated expression of D3 in the skin suggest the possibility of a cross-talk between thyroid hormone and Shh signaling in BCCs, a mechanism that could have broad implications and may led to the identification of novel therapeutic approaches aimed at interfering with these pathways in a pathological context. Aim of this study was to characterize the role of D3 in skin tumorigenesis and determine the mechanisms by which D3 depletion or T3 treatment interfere with proliferation in a skin model cancer.